The race to build isotopes better

Nuclear imaging has revolutionized how we diagnose and treat life-threatening diseases. But the technology requires a reliable supply of isotopes to produce the high-quality images. Canada had it, but nearly lost it, throwing the nuclear imaging ﬁeld into crisis. The federal government wants to ensure that doesn’t happen again.

The city of Richmond is home to a leading global manufacturer of particle accelerator equipment to produce radioactive materials, Advanced Cyclotron Systems Inc. This firm, known as ACSI, has contributed significantly to the development of TRIUMF, Canada’s national subatomic physics laboratory, located a short drive away on the University of British Columbia campus. You could easily drive past the unimposing facades of either of these enterprises without noticing them.

Nevertheless, in a warehouse at the rear of the ACSI lot, behind piles of scrap metal and vehicles lugging large girders, are several high-tech marvels in their final phases of testing. These are state-of-the-art cyclotrons, some of them the size of a single-car garage.

Among ACSI’s accomplishments has been construction of the world’s largest cyclotron, the centrepiece of TRIUMF’s operation, featuring a 4,000-tonne magnet 18 metres in diameter. It dominates a vast space the size of a football field, three storeys below a building at UBC, shielded by three layers of 100-tonne concrete blocks.

Cyclotrons employ powerful magnets to accelerate negatively charged hydrogen atoms up to science-fiction velocities – perhaps as much as three-quarters of the speed of light, which could take you to the moon and back in a matter of two seconds. The particles are then directed in beams that collide with metal targets resembling oversized coins. These targets are transformed into isotopes – radioactive versions of that metal or of another element altogether.

With their proven expertise, TRIUMF and ACSI are among the 15 Canadian organizations that are sharing $35 million in federal funding in four distinct projects with an urgent timeline. The goal of all of them is to find a guaranteed way for hospitals to have access to Technetium-99m, the radioactive isotope crucial to the most sophisticated forms of medical imaging. This isotope can be safely injected into the human body, yielding high-resolution images of structures, like tumors or abscesses, as well as the physiological activity taking place around these sites. The result: a powerful diagnostic tool in fields like cardiology and oncology, where it can determine treatments for life-threatening conditions. The tool transcends and complements the capabilities of other systems for medical visualization, such as X-rays, Computerized Axial Tomography (CAT scanning), or Magnetic Resonance Imaging (MRI). And until recently, physicians and patients took the supply of those isotopes for granted.

Not long ago, the work of cyclotrons mainly interested people working within a narrowly defined range of scientific disciplines. That changed after Canada’s great “isotope crisis” a few years ago. A smoothly running system that had provided medical isotopes to hospitals for decades was thrown into disarray at the end of 2007, when an aging nuclear reactor, National Research Universal, or NRU, broke down and safety issues were uncovered.

Installed in the nuclear heyday of the 1950s at Chalk River, Ontario, 180 km northwest of Ottawa, the NRU was intended as a research tool, with a very different design from the reactors found in power-generating stations around the world. But, in spite of its scientific mandate, by the 1970s it was efficiently turning particular types of metals into short-lived radioactive species that were ideal for commercial applications. One of its achievements was supplying more than half of the world’s Technetium-99m.

When the NRU went out of commission, clinicians throughout Canada and the U.S. were forced to delay or cancel imaging sessions, raising the frightening prospect that patients’ care would be compromised. There are only a handful of reactors suited to producing these kinds of isotopes in the world – mostly in far-flung locations that include the Netherlands, South Africa, Australia and South Korea – and, like Chalk River, some of these facilities are nearing the end of their operating lives.

As it happened, a brief breakdown of the NRU in the early 1990s had already led its managers to seek a way of avoiding any future interruption in isotope production. A pair of reactors, called MAPLE (for Multipurpose Applied Physics Lattice Experiment), were assembled at Chalk River in the late ’90s, intended for service early this century. But testing raised questions about their stability and safety. Those questions were never resolved and, after more than a decade and more than $800-million spent on the initiative, MAPLE was officially abandoned in 2008.

Today, there are few lingering signs of the isotope crisis in hospitals and clinics across Canada. The Chalk River reactor was finally mended in 2010 and the output of isotopes restored. Yet the fix is far from permanent. Already more than 50 years old, the reactor is scheduled to retire in 2016. Nordion Inc. – the multinational isotope distributor based in Ottawa that once made exclusive use of the NRU for medical isotopes – has started looking elsewhere for its supply. The company has turned to Rosatom, a Russian state-owned corporation that builds nuclear reactors, to supply a growing portion of its inventory from installations in the former Soviet Union.

Meanwhile, the Chalk River situation was termed a catastrophe by the Canadian medical establishment, who demanded an immediate solution to meet short-term demand as well as a new system to provide a continuous, reliable supply of isotopes in the future. That’s why, early last year, Natural Resources Canada formally announced the participants in its Non-reactor Isotope Supply Contribution Program, dubbed NISP. The list makes for a who’s who of medical isotope users across the country. They are pursuing the four major projects that could lead to new ways of supplying medical isotopes. The perceived urgency of the isotopes crisis prompted a tight, 15-month deadline: final reports are due in March of this year.

The four projects represent an extraordinary collaboration among Canadian researchers from hospitals, universities and private firms. Two separate projects led by TRIUMF and by ACSI are looking at ways of tapping into cyclotrons that are already installed at hospitals across the country. The other two projects are led by Canadian Light Source Inc. at the University of Saskatchewan and by a Winnipeg consortium called Prairie Isotope Production Enterprise. These last two are exploring the potential of systems called linear accelerators that send charged particles in a straight line (rather than circles as in the cyclotron), dramatically simplifying the process.

Paul Schaffer, deputy head of nuclear medicine for TRIUMF, says, “Networking was absolutely crucial. There is no single group that can tackle a project of this magnitude.” TRIUMF, for example, is aligned with 16 universities.

The potential cyclotron network. Each node represents an exisiting or planned cyclotron facility, ringed by the size of area it could serve, by road and air. The darker circles indicate the distance served if the isotopes were transported by car or truck (4 hours). The larger circles in red indicate the distance served if the isotopes were transported by plane (2 hours). Source: Advanced Cyclotron Systems Inc.

Most of the researchers who responded to the call from government after the isotope crisis already had some connection with one another, says Dr. Schaffer. “The relationships were primed, and then this situation just kicked in.”

The focus, in each project, is to come up with a cost-effective, safe and reliable way of domestically supplying isotopes without the cost of building nuclear reactors or the need to use weapons-grade uranium and produce nuclear waste. The technology exists, but implementing it would be a major departure from clinical practices used for decades. The result would be a revolution in the field of medical imaging – yet an invisible one to most Canadians who need this important service. The same machinery would be in place at hospitals and clinics, using the same key isotope, Technetium-99m.

The importance of Technetium-99m in modern nuclear medicine cannot be overstated. Technetium-99m’s isotopes emit large amounts of electromagnetic energy, known as gamma rays, primarily during a short half-life of about six hours. This brief exposure minimizes any risk to the human body, but for the few hours it remains active it offers an unrivaled opportunity to look around. Even dynamic activities, like blood flow or drug interactions, are visible with Single Photon Emission Computed Tomography (SPECT) cameras.

Throughout the 1980s and 1990s, SPECT became a workhorse technology in labs and clinics around the world. And Canada’s Nordion, by offering a steady and reasonably priced supply of much longer-lived isotopes, dominated the global market. The long-lived, reactor-produced isotopes remain viable for several days and thus have been crucial to Nordion’s ability to ship to destinations across North America and beyond.

Soon after the isotope crisis, members of TRIUMF began discussing the virtue of producing Technetium-99m with cyclotrons that are already in use at Canadian hospitals and clinics, instead of at a nuclear reactor. The feasibility of that idea is what is being formally assessed through the $35 million in government funding.

Among the organizations involved with TRIUMF is the Lawson Health Research Institute in London, Ontario, which manages its own cyclotron facility. Lawson staff were already well-practised in producing isotopes for another type of medical scanning instrument, known as Positron Emission Tomography (PET). But this process is more onerous for clinics and hospitals, explains Michael Kovacs, an imaging scientist at Lawson.

In the system currently in use in Canadian clinics and hospitals, when a package containing isotopes arrives, staff members activate a simple desktop “generator” to chemically convert the material into Technetium-99m shortly before a patient’s arrival. The entire process has been approved by Health Canada; Nordion handles the extensive paperwork required by the federal government for a compound that will be injected into patients.

But at sites like Lawson, local staff must take on this time-consuming task. “Each of these sites becomes its own manufacturing entity,” says Dr. Kovacs, and each must provide a full accounting of their manufacturing practices to Health Canada.

Moreover, Technetium-99m produced by a cyclotron has a useful shelf life of just a few hours, in contrast to 60 hours for a reactor-produced isotope. This means that a cyclotron facility could serve only destinations within a few hundred kilometres. Clinics or hospitals without nearby cyclotrons either would have to continue to rely on isotopes from reactors, or their patients would have to travel to larger centres for imaging diagnosis.

The second NISP-funded cyclotron project, led by ACSI, is working with clinical centres associated with the University of Alberta and Université de Sherbrooke, where the company’s machines have already been installed. The goal is the same: find a way to replace reactors for isotope production.

That goal is especially important to Eric Turcotte, a clinician-researcher at Université de Sherbrooke and a member of an expert panel that advised the federal government on its options in the wake of the Chalk River shutdown. Now head of the Sherbrooke Molecular Imaging Centre, he has had a front-row seat to observe the growing use of cyclotrons for medical imaging since the 1990s.

Dr. Turcotte says it is entirely feasible to replace reactor-produced isotopes with those from cyclotrons; this past November, the first two patients received Technetium-99m generated by a cyclotron from the Cross Cancer Institute in Edmonton. But, in addition to the logistical hurdle that could force some patients to travel to imaging centres that are close to cyclotrons, there is another fundamental catch: the price.

Although the $20-million price of a cyclotron is a fraction of the cost of building a nuclear reactor, the latter is usually constructed and maintained by a government agency. This was the case with NRU at Chalk River and is the case with Rosatom’s reactors in Russia, so Nordion can import isotopes at a lower cost than what the Canadian cyclotron sources would have to charge.

The two linear accelerator projects funded by NISP are addressing this challenge with a simpler, less expensive system. Although these instruments are less powerful than most cyclotrons, they might be able to do the job just as well, particularly in places that aren’t near a cyclotron and don’t want to invest in one. But linear accelerators have seldom found widespread use in medical imaging circles, so these projects (led by the Canadian Light Source in Saskatoon and the Prairie Isotope Production Enterprise in Winnipeg) have called for new dedicated facilities and have not progressed as quickly as the two cyclotron projects.

This past November, all four projects confirmed that each would have its feasibility study ready for the government by March. At a workshop in Ottawa, they all promised a full slate of results, including answers to technical questions on whether reactors can really be replaced by cyclotrons or linear accelerators. But a larger question haunts Dr. Turcotte: what if the discussion ends with the tabling of their studies? If isotopes continue to make their way from Chalk River or Russia to Canadian patients, there could be little incentive to consider more costly strategies.

And make no mistake, he warns: the federal government would have to decide to assume some of the costs of building a Canadian network of isotope-producing cyclotrons for it to have even a chance of success. “If the Technetium from subsidized reactors is available on the market for many years, it will be very hard for accelerator technology to find a market.”

But he expects that eventually an incentive will emerge. If nothing else, when the Chalk River facility is shuttered for good in 2016, likely there will be complaints about relying on foreign suppliers for an important Canadian medical commodity. And everyone who took part in NISP will remain a highly motivated player. “The government will know that the cyclotron is an available technology,” says Dr. Turcotte. “I think it will stay quiet for many years, until the next shortage.”

TRIUMF’s Paul Schaffer expects things to remain just as quiet out on British Columbia’s cyclotron coast. But, nevertheless, he and his colleagues eagerly look forward to ushering in an imaging revolution, even if it remains invisible to most Canadians. The need for this technology is too pressing, he says. “We have to demonstrate a process of isotope production at the commercial scale. This has never been done before, even if it’s been done at the research scale.”

And the learning opportunity, he adds, is simply irresistible: “What are the risks, where could it potentially fail and how can we control those as best as we can?”

Tim Lougheed, based in Ottawa, is past president of the Canadian Science Writers’ Association. His research for this article was supported by a CIHR Journalism Award.

In this article, posted Feb. 6, 2012, several sentences have been rewritten to correct errors. The Canadian company Nordion – which changed its name from MDS Nordion in 2010 – does not directly supply the Canadian market with medical isotopes, nor does it ship isotopes directly to hospitals. Nordion processes radiochemicals into medical isotopes which it supplies to radiopharmaceutical manufacturers. Also, some patients received Technetium-99m generated by a cyclotron at the Cross Cancer Institute in Edmonton, not at Université de Sherbrooke.

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